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Can we identify people with Alzheimer's disease from examination of the eye? A bidirectional Mendelian randomization (MR) study.

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Title: Can we identify people with Alzheimer's disease from examination of the eye? A bidirectional Mendelian randomization (MR) study.
Authors: Kiser H; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, UK; Department of Statistics, Comilla University, Cumilla, Bangladesh., Budu-Aggrey A; Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK., Bailey JNC; Center for Health Disparities, Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA; Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA., Villaplana-Velasco A; Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Bernabeu MO; Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, Scotland, UK; The Bayes Centre, The University of Edinburgh, Edinburgh, Scotland, UK., Jiang X; UCL Institute of Ophthalmology, London. UK; UCL Great Ormond Street Institute of Child Health, University College London, London, UK., Owen CG; Population Health Research Institute, City St. George's, University of London, London, UK., Haines JL; Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA., Pasquale LR; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY USA., MacGregor S; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Gao XR; Departments of Ophthalmology and Visual Science and Biomedical Informatics, Division of Human Genetics, The Ohio State University, Columbus, OH 43212, USA., Wiggs JL; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA., Jiang C; Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA., Choquet H; Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA; Department of Health Systems Science Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA., Smith GD; Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK., Kehoe PG; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, UK., Davies NM; Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, 7034 Trondheim, Norway; Department of Statistical Science, University College London, London, UK; Division of Psychiatry, University College London, London, UK., Hanson AL; Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK., Anderson EL; Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Division of Psychiatry, University College London, London, UK., Atan D; School of Neuroscience and Psychology, University of Bristol, Bristol, UK; Bristol Eye Hospital, University Hospitals Bristol & Weston NHS Foundation Trust, Bristol, UK. Electronic address: denize.atan@bristol.ac.uk.
Corporate Authors: NEIGHBORHOOD consortium, International Glaucoma Genetics Consortium, UK Biobank Eye and Vision Consortium
Source: The journal of prevention of Alzheimer's disease [J Prev Alzheimers Dis] 2026 Oct; Vol. 13 (8), pp. 100635. Date of Electronic Publication: 2026 Jul 10.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Springer International Publishing Country of Publication: United States NLM ID: 101638820 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2426-0266 (Electronic) Linking ISSN: 22745807 NLM ISO Abbreviation: J Prev Alzheimers Dis Subsets: MEDLINE
Imprint Name(s): Publication: <2018>: [Cham, Switzerland] : Springer International Publishing
Original Publication: Auzeville-Tolosane : SERDI éd., [2014]-
MeSH Terms: Alzheimer Disease*/genetics , Alzheimer Disease*/diagnosis , Mendelian Randomization Analysis*, Humans ; Genome-Wide Association Study ; Tomography, Optical Coherence ; Male
Abstract: Background: Neurodegeneration in Alzheimer's disease (AD) is thought to be driven by amyloid-beta and tau deposition in the cerebral vasculature and brain. As the eye is an extension of the central nervous system, this study aimed to determine which neurovascular and neuroretinal changes in the eye are caused by AD rather than associations of the disease.
Methods: Bidirectional two-sample univariable and multivariable Mendelian randomization (MR) methods were applied. Instrumental variables were derived from genome-wide association studies (GWAS) of AD and the following ocular features: thickness measurements of central macula (MT), retinal nerve fibre layer (mRNFL), ganglion cell-inner plexiform layer (mGCIPL), outer nuclear layer (ONL), inner segment layer (IS), and outer segment (OS) from macular region OCT scans; arteriolar tortuosity (AT), venular tortuosity (VT), venular width (VW), fractal dimension (FD), vertical cup-to-disc ratio (VCDR), optic cup area (OCA), and optic disc area (ODA) derived from other imaging methods.
Results: There was strong evidence that genetic liability to AD affected the retinal vasculature by specifically increasing AT (β = 0.007;95%CI=0.002,0.011;p-value=0.005) in UK Biobank participants (n=52,798). AD may influence the mRNFL (β=-0.047,95%CI=-0.119,0.023,p-value=0.18) and mGCIPL (β=-0.061;95%CI=-0.14,0.025,p-value=0.16) of the inner retina and OS layer (β = 0.044;95%CI=-0.0001,0.08;p-value=0.05) but the evidence was weak. Multivariable MR analysis showed that a causal relationship between optic disc area and AD (OR=0.76;95%CI=0.62,0.93,p-value=0.009) was probably mediated by refractive error.
Conclusion: Early cerebrovascular signs of AD may be detected by examination of the eye. Further investigation is required to determine the clinical utility of eye screening for dementia.
(Copyright © 2026 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Competing Interests: Declaration of competing interest DA is on the clinical advisory board of Siloton Ltd. GDS reports grants from the MRC Integrative Epidemiology Unit at the University of Bristol; he is a member of the Scientific Advisory Board for Bristol Myers Squibb, Relation Therapeutics and Insitro. JLW reports consulting fees from Editas and CRISPR Therapeutics. MOB reports research grants from Gates Ventures, LifeArc, Eisai, Wellcome Leap, Optos and UKRI; and consulting fees from LifeArc. SM is a director of Seonix Pty Ltd, a company commercialising polygenic risk scores, and he holds equity in Seonix Pty Ltd. HK, ABA, JNCB, AVV, XJ, CGO, JLH, LRP, XRG, CJ, HC, PGK, NMD, ALH, and ELA have no conflicts of interest.
Grant Information: R01 EY015473 United States EY NEI NIH HHS; R01 EY022305 United States EY NEI NIH HHS; R01 EY033829 United States EY NEI NIH HHS
Contributed Indexing: Keywords: Alzheimer’s disease; Mendelian randomization; Optic disc; Retina; Vasculature
Entry Date(s): Date Created: 20260710 Date Completed: 20260915 Latest Revision: 20260915
Update Code: 20260916
PubMed Central ID: PMC13380462
DOI: 10.1016/j.tjpad.2026.100635
PMID: 42430965
Database: MEDLINE
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  Data: Can we identify people with Alzheimer&#39;s disease from examination of the eye? A bidirectional Mendelian randomization (MR) study.
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  Data: &lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Kiser+H%22&quot;&gt;Kiser H&lt;/searchLink&gt;; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, UK; Department of Statistics, Comilla University, Cumilla, Bangladesh.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Budu-Aggrey+A%22&quot;&gt;Budu-Aggrey A&lt;/searchLink&gt;; Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Bailey+JNC%22&quot;&gt;Bailey JNC&lt;/searchLink&gt;; Center for Health Disparities, Department of Pharmacology &amp; Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA; Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Villaplana-Velasco+A%22&quot;&gt;Villaplana-Velasco A&lt;/searchLink&gt;; Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, The Queen&#39;s Medical Research Institute, University of Edinburgh, Edinburgh, UK.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Bernabeu+MO%22&quot;&gt;Bernabeu MO&lt;/searchLink&gt;; Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, Scotland, UK; The Bayes Centre, The University of Edinburgh, Edinburgh, Scotland, UK.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Jiang+X%22&quot;&gt;Jiang X&lt;/searchLink&gt;; UCL Institute of Ophthalmology, London. UK; UCL Great Ormond Street Institute of Child Health, University College London, London, UK.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Owen+CG%22&quot;&gt;Owen CG&lt;/searchLink&gt;; Population Health Research Institute, City St. George&#39;s, University of London, London, UK.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Haines+JL%22&quot;&gt;Haines JL&lt;/searchLink&gt;; Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Pasquale+LR%22&quot;&gt;Pasquale LR&lt;/searchLink&gt;; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY USA.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22MacGregor+S%22&quot;&gt;MacGregor S&lt;/searchLink&gt;; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Gao+XR%22&quot;&gt;Gao XR&lt;/searchLink&gt;; Departments of Ophthalmology and Visual Science and Biomedical Informatics, Division of Human Genetics, The Ohio State University, Columbus, OH 43212, USA.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Wiggs+JL%22&quot;&gt;Wiggs JL&lt;/searchLink&gt;; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Jiang+C%22&quot;&gt;Jiang C&lt;/searchLink&gt;; Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Choquet+H%22&quot;&gt;Choquet H&lt;/searchLink&gt;; Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA; Department of Health Systems Science Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Smith+GD%22&quot;&gt;Smith GD&lt;/searchLink&gt;; Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Kehoe+PG%22&quot;&gt;Kehoe PG&lt;/searchLink&gt;; Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, UK.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Davies+NM%22&quot;&gt;Davies NM&lt;/searchLink&gt;; Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, 7034 Trondheim, Norway; Department of Statistical Science, University College London, London, UK; Division of Psychiatry, University College London, London, UK.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Hanson+AL%22&quot;&gt;Hanson AL&lt;/searchLink&gt;; Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Anderson+EL%22&quot;&gt;Anderson EL&lt;/searchLink&gt;; Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Division of Psychiatry, University College London, London, UK.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Atan+D%22&quot;&gt;Atan D&lt;/searchLink&gt;; School of Neuroscience and Psychology, University of Bristol, Bristol, UK; Bristol Eye Hospital, University Hospitals Bristol &amp; Weston NHS Foundation Trust, Bristol, UK. Electronic address: denize.atan@bristol.ac.uk.
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  Data: Background: Neurodegeneration in Alzheimer&#39;s disease (AD) is thought to be driven by amyloid-beta and tau deposition in the cerebral vasculature and brain. As the eye is an extension of the central nervous system, this study aimed to determine which neurovascular and neuroretinal changes in the eye are caused by AD rather than associations of the disease.&lt;br /&gt;Methods: Bidirectional two-sample univariable and multivariable Mendelian randomization (MR) methods were applied. Instrumental variables were derived from genome-wide association studies (GWAS) of AD and the following ocular features: thickness measurements of central macula (MT), retinal nerve fibre layer (mRNFL), ganglion cell-inner plexiform layer (mGCIPL), outer nuclear layer (ONL), inner segment layer (IS), and outer segment (OS) from macular region OCT scans; arteriolar tortuosity (AT), venular tortuosity (VT), venular width (VW), fractal dimension (FD), vertical cup-to-disc ratio (VCDR), optic cup area (OCA), and optic disc area (ODA) derived from other imaging methods.&lt;br /&gt;Results: There was strong evidence that genetic liability to AD affected the retinal vasculature by specifically increasing AT (β = 0.007;95%CI=0.002,0.011;p-value=0.005) in UK Biobank participants (n=52,798). AD may influence the mRNFL (β=-0.047,95%CI=-0.119,0.023,p-value=0.18) and mGCIPL (β=-0.061;95%CI=-0.14,0.025,p-value=0.16) of the inner retina and OS layer (β = 0.044;95%CI=-0.0001,0.08;p-value=0.05) but the evidence was weak. Multivariable MR analysis showed that a causal relationship between optic disc area and AD (OR=0.76;95%CI=0.62,0.93,p-value=0.009) was probably mediated by refractive error.&lt;br /&gt;Conclusion: Early cerebrovascular signs of AD may be detected by examination of the eye. Further investigation is required to determine the clinical utility of eye screening for dementia.&lt;br /&gt; (Copyright &#169; 2026 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
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  Data: Declaration of competing interest DA is on the clinical advisory board of Siloton Ltd. GDS reports grants from the MRC Integrative Epidemiology Unit at the University of Bristol; he is a member of the Scientific Advisory Board for Bristol Myers Squibb, Relation Therapeutics and Insitro. JLW reports consulting fees from Editas and CRISPR Therapeutics. MOB reports research grants from Gates Ventures, LifeArc, Eisai, Wellcome Leap, Optos and UKRI; and consulting fees from LifeArc. SM is a director of Seonix Pty Ltd, a company commercialising polygenic risk scores, and he holds equity in Seonix Pty Ltd. HK, ABA, JNCB, AVV, XJ, CGO, JLH, LRP, XRG, CJ, HC, PGK, NMD, ALH, and ELA have no conflicts of interest.
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  Data: R01 EY015473 United States EY NEI NIH HHS; R01 EY022305 United States EY NEI NIH HHS; R01 EY033829 United States EY NEI NIH HHS
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              Y: 2026
          Identifiers:
            – Type: issn-electronic
              Value: 2426-0266
          Numbering:
            – Type: volume
              Value: 13
            – Type: issue
              Value: 8
          Titles:
            – TitleFull: The journal of prevention of Alzheimer's disease
              Type: main
ResultId 1